1. Field of the Invention
The invention generally concerns the fields of medicine and molecular biology. In particular, the invention concerns polypeptides for delivery of therapeutic molecules and methods for the use thereof.
2. Description of Related Art
Cancer, metabolic and infectious diseases, and other diseases are caused by the inappropriate activity of specific genes. The ability to silence genes selectively through RNA interference (RNAi) offers the potential to revolutionize the way diseases and illnesses are treated, by creating a new class of drugs aimed at eliminating specific gene-products or proteins from the cell. RNAi has been convincingly demonstrated in preclinical models of oncology, influenza, hepatitis, diabetes, macular degeneration, Parkinson's disease, Huntington's disease and many other areas of serious unmet medical need.
RNA interference, based upon the use of short interfering RNA (siRNA) duplexes, has many advantages for rapid development of an effective therapeutic agent. Based on the mRNA sequence for the target protein, siRNA therapeutics can be designed relatively quickly (compared to the time needed to synthesize and screen conventional small molecule drugs). Further, siRNA-based therapeutics can be designed to possess great specificity to the target mRNA of interest.
Several delivery vehicles that target siRNA to tumors are in clinical trials, yet have not been approved by the FDA (Castanotto and Rossi, 2009, Nature 457: 426-33; Zimmermann et al., 2006, Nature 441: 111-4). In these trials, systemic administration of siRNA with non-targeted nanoparticles could result in dose-dependent tumor accumulation and silencing of target gene expression (Juhasz et al., 2006, Oncol Rep. 15: 1299-304.). Despite these encouraging data, the genes targeted by these siRNAs are expressed in all normal cells, albeit at lower levels than in many tumor cells (Cerqueira et al., 2005, Curr Med Chem. 12: 1283-94; Heidel et al., 2007, Proc Natl Acad Sci USA. 104: 5715-21). A further common drawback to using non-targeting nanoparticles is their significant accumulation in the liver, kidney and spleen, leading to potential off-target effects and reducing effective doses of therapeutic payload to other organs.
RNA is rapidly degraded by RNA nucleases in the body, and siRNA drugs must be protected from these enzymes by encapsulating in a nanoparticle that can increase the concentration of the nucleotide in the circulating blood. The disadvantage of using siRNA is its rapid degradation by nucleases in the circulation. The primary challenge to the use of siRNAs as therapeutics in mammals is the intracellular delivery of intact siRNA to specific tissues and organs that express the target gene. Two important factors are essential for successful use of siRNA to treat disease: (1) selecting a specific genetic target responsible for promotion of the particular disease, and (2) a method of targeting the siRNA directly to the diseased cells. In cancer treatment, for example, selecting a specific oncogene as a siRNA target, and a method of targeting the siRNA directly to tumor cells.
However, these essential targeting factors have not yet been achieved. Thus there remains a need in the art for reagents and methods for targeted delivery of siRNA (and other drug molecules) to cells, particularly cancer cells, to improve their therapeutic effectiveness.